Each of the applications and patents cited in this text, including each of the foregoing cited applications, as well as each document or reference cited in each of the applications and patents (including during the prosecution of each issued patent; xe2x80x9capplication cited documentsxe2x80x9d), and each of the PCT and foreign applications or patents corresponding to and/or claiming priority from any of these applications and patents, and each of the documents cited or referenced in each of the application cited documents, are hereby expressly incorporated herein by reference. More generally, various documents or references are cited in this text, either in a Reference List before the claims or in the text itself; and, each of the documents or references (xe2x80x9cherein cited documentsxe2x80x9d) and all of the documents cited in this text (also xe2x80x9cherein cited documentsxe2x80x9d), as well as each document or reference cited in each of the herein cited documents (including any manufacturer""s specifications, instructions, etc. for products mentioned herein and in any document incorporated herein by reference), is hereby expressly incorporated herein by reference. There is no admission that any of the various documents cited in this text are prior art as to the present invention. Any document having as an author or inventor person or persons named as an inventor herein is a document that is not by another as to the inventive entity herein. Also, teachings of herein cited documents and documents cited in herein cited documents and more generally in all documents incorporated herein by reference can be employed in the practice and utilities of the present invention.
The invention relates to a new crystalline form of 3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one, herein designated as xe2x80x9cPolymorphic Form B or Polymorph Bxe2x80x9d, with pharmaceutically acceptable bases, which are inhibitors of cyclooxygenase-2 and useful as non-steroidal antiinflammatory drugs.
In another aspect, the invention relates to pharmaceutical compositions and methods of making and using the Polymorph B of 3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one.
The invention also relates to a method for preparing polymorphic Form B comprising agitating polymorphic Form A in the presence of methanol.
The invention also relates to a method for preparing polymorphic Form B comprising agitating polymorphic Form A in the presence of polymorphic Form B seeds in methanol.
Non-steroidal antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase.
Two forms of cyclooxygenase are known, corresponding to cyclooxygenase-1 (COX-1) or the constitutive enzyme, as originally identified in bovine seminal vesicles, and a second inducible form of cyclooxygenase, cyclooxygenase-2 (COX-2) which has been cloned, sequenced and characterized initially from chicken, murine and human and animal sources. This enzyme is distinct from the COX-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, it was concluded that the constitutive enzyme, COX-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, it was concluded that the inducible form, COX-2 is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of COX-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer and anti-angiogenic effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects and a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
Furthermore, such a compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of premature labour, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer""s disease, for decreasing bone loss particularly in postmenopausal women (i.e. treatment of osteoporosis) and for the treatment of glaucoma. It may also be useful for the treatment of age-related dementia, for decreasing osteoclastic bone loss and for treatment of glaucoma
A brief description of the potential utility of cyclooxygenase-2 inhibitors is given in an article by John Vane, Nature, Vol. 367, pp. 215-216, 1994, and in an article in Drug News and Perspectives, Vol. 7, pp. 501-512, 1994.
Compounds having a potent COX-2 inhibitory effect are disclosed in WO 97/44027, WO 97/28121, WO 98/41516, WO 97/16435 and WO 97/14691.
WO 97/14691 discloses methylsulfonylphenyl-5H-furan-2-one compounds which are potent COX-2 inhibitors, namely 3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one which was isolated in a crystalline form which is herein designated as xe2x80x9cPolymorphic Form A or Polymorph Axe2x80x9d.
The formula of 3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one is the following. 
Recrystallization of polymorph A for purification purposes leaded to solubility problems in methyltertiobutylether.
Mixtures of 3-(cyclopropylmethoxy)-4-(4-methylsulfonyl)phenyl-5,5-dimethylfuranone solid at 6.3% weight in methyltertiobutylether could no longer be solubilised. After dilution and recrystallization, the powder obtained was analysed by X-Ray diffraction and showed a different pattern than the initial product.
The experiment was reproduced in several solvents such as methanol and dimethylformamide. The new solid form obtained was named polymorph B.
In a first embodiment the invention provides 3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one in Polymorphic Form B, which is useful as a xe2x80x9cnon steroidal antiinflammatory agentxe2x80x9d for the treatment of cyclooxygenase-2 mediated diseases.
Polymorph B possesses better flow characteristics than Polymorph A and is thermodynamically more stable than Polymorph A. Thus, Polymorph B is easier to handle (remove from vessel and transfer to filter), filter and dry than Polymorph A. Polymorph B is also easier to feed and micronize. Hence, the methods for its manufacture are more easily validated than that of Polymorph A.
Polymorph B may be characterized by the following parameters:
Polymorph B may be further be characterized by the following X-ray diffraction data calculated from crystalline structure.
By way of comparison, the parameters and the X-ray diffraction data calculated from crystalline structure of polymorph A are reported hereunder:
The powder X-ray diffraction pattern of polymorphs A and B is described hereafter in greater detail with respect to the enclosed figures.